This proposed research is intended to identify and understand mechanisms which initiate and orchestrate the hypermetabolic, inflammatory reaction which is regularly produced by burn injury. As a result of these studies, it is intended that methods can be developed which modulate the inflammatory reaction. The overall hypothesis of the Burn Trauma Center studies is that the inflammatory reaction can exceed its beneficial effects and become self-injuring. Studies will identify structural and functional alterations at the cellular level which allow the initiation, amplification, and maintenance of the reaction to injury. In Project 1, investigations will address the induction, modulation, and effects of the soluble inflammatory mediators including C5a, C3a, IL-1, TNF, and related molecules to the inflammatory response seen in burn injury. In Project II, in order to better understand the initiation and maintenance of the hypermetabolic response, proposed studies will examine the hypothesis that the hypermetabolism involving amino acid, glucose, and energy turnover produces relative insufficiencies of dispensable amino acids which make these amino acids conditionally indispensable or essential after burn injury. During extensive increases in protein turnover, the insufficient de novo synthesis of these amino acids is rate-limiting for protein synthesis and further promotes amino acid mobilization via skeletal muscle catabolism. These studies will utilize steady-state kinetic tracer and analytical methods involving mass spectroscopy, nuclear magnetic spectroscopy, cyclotron-generated metabolites, and metabolic mathematical modeling techniques. These new, innovative and sensitive methodologies will allow less invasive patient studies at the regional, organ, and cellular level. In Project III, not only will the generation and control of inflammatory mediators and their metabolic effects be studied but their consequences will be considered on the structure and barrier function of a target organ, the gut. Enhanced gut permeability represents a fundamental failure of the gut which could be transient in nature but whose magnitude and duration could be enhanced by "second injuries" including infection, malnutrition, and immunosuppression. It is possible that the currently unknown but detailed mechanism(s) involved in permeability of the gut epithelium likely involves the direct or indirect effects of mediators of the acute inflammatory response.